The present invention relates to epothilone A, epothilone B, epothilone analogs, libraries of epothilone analogs, and methods for producing such compounds using solid phase and solution phase chemistries.
Epothilone A (1, FIG. 1) and epothilone B (2, FIG. 1) are natural substances isolated from myxobacteria Sorangium cellulosum strain 90. These natural substances exhibit cytotoxicity against taxol-resistant tumor cells and may prove to have a clinical utility comparable or superior to Taxol. (For Taxol references see: Horwitz et al. Nature 277, 665-667 (1979); Nicolaou et al. Angew. Chem. Int. Ed. Engl. 33, 15-44 (1994).) Like taxol, the epothilones are thought to exert their cytotoxicity by induction of microtubule assembly and stabilization. (Bollag et al. Cancer Res. 55, :2325-2333 (1995); Kowalski et al. J. Biol. Chem. 272, 2534-2541 (1997).) Epothilones are reported to be about 2000-5000 times more potent than Taxol with respect to the stabilization of microtubules. Despite the marked structural differences between the epothilones and Taxol(trademark), the epothilones were found to bind to the same region on microtubules and to displace Taxol(trademark) from its binding site. (Grever et al. Seminars in Oncology 1992, 19, 622-638; Bollag et al. Cancer Res. 1995, 55, 2325-2333; Kowalski et al. J. Biol. Chem. 1997, 272, 2534-2541; Horwitz et al. Nature 1979, 277, 665-667; Nicolaou et al. Angew. Chem. Int. Ed. Engl. 1994, 33, 15-44.) Epothilones A and B have generated intense interest amongst chemists, biologists and clinicians due to their novel molecular architecture, important biological action and intriguing mechanism of action. (Hxc3x6fle et al. Angew. Chem. Int. Ed. Engl. 35, 1567-1569 (1996); Grever et al. Semin. Oncol. 19, 622-638 (1992); Bollag et al. Cancer Res. 55, 2325-2333 (1995); Kowalski et al. J. Biol. Chem. 272, 2534-2541 (1997); Nicolaou et al. Angew. Chem. Int. Ed. Engl. 35, 2399-2401 (1996); Meng et al. J. Org. Chem. 61, 7998-7999 (1996); Bertinato et al. J. Org. Chem. 61, 8000-8001 (1996); Schinzer et al. Chem. Eur. J. 2, 1477-1482 (1996); Mulzer et al. Tetrahedron Lett. 37, 9179-9182 (1996); Claus et al. Tetrahedron Lett. 38, 1359-1362 (1997); Gabriel et al. Tetrahedron Lett. 38, 1363-1366 (1997); Balog et al. Angew. Chem. Int. Ed. Engl. 35, 2801-2803 (1996); Yang et al. Angew. Chem. Int. Ed. Engl. 36, 166-168 (1997); Nicolaou et al. Angew. Chem. Int. Ed. Engl. 36, 525-527 (1997); Schinzer et al. Angew. Chem. Int. Ed. Engl. 36, 523-524 (1997); Meng et al. J. Am. Chem. Soc. 119, 2733-2734 (1997).)
What is needed are analogs of epothilone A and B and libraries of analogs of epothilone A and B that exhibit superior pharmacological properties in the area of microtubule stabilizing agents.
What is needed are methods for producing synthetic epothilone A, epothilone B, analogs of epothilone A and B, and libraries of epothilone analogs, including epothilone analogs possessing both optimum levels of microtubule stabilizing effects and cytotoxicity.
The invention is directed to epothilone analogs and processes and intermediates for making same.
One aspect of the invention is directed to an epothilone analog represented by the following structure: 
In a preferred embodiment, n is one. However, in alternative embodiments n may be as large as five. R1 is a radical selected from the group consisting of hydrogen, tert-butyldimethylsilyl, trimethylsilyl, methyl, acetyl, benzoyl, and tert-butoxycarbonyl. R2 is a radical selected from the group consisting of hydrogen, tert-butyldimethylsilyl, trimethylsilyl, methyl, acetyl, benzoyl, and tert-butoxycarbonyl. R3 is a radical selected from the group consisting of hydrogen, methyl, xe2x80x94CHO, xe2x80x94COOH, xe2x80x94CO2Me, xe2x80x94CO2 (tert-butyl), xe2x80x94CO2 (iso-propyl), xe2x80x94CO2 (phenyl), xe2x80x94CO2 (benzyl), xe2x80x94CONH(furfuryl), xe2x80x94CO2 (N-benzo-(2R, 3S)-3-phenylisoserine), xe2x80x94CONH(methyl)2, xe2x80x94CONH(ethyl)2, xe2x80x94CONH(benzyl), and xe2x80x94CH2R5. R5 is a radical selected from the group consisting of xe2x80x94OH, xe2x80x94O-Trityl, xe2x80x94Oxe2x80x94(C1-C6 alkyl), xe2x80x94O-benzyl, xe2x80x94O-allyl, xe2x80x94Oxe2x80x94COCH3, xe2x80x94Oxe2x80x94COCH2Cl, xe2x80x94Oxe2x80x94COCH2CH3, xe2x80x94Oxe2x80x94COCF3, xe2x80x94Oxe2x80x94COCH (CH3)2, xe2x80x94Oxe2x80x94COC(CH3)3, xe2x80x94Oxe2x80x94CO(cyclopropane), xe2x80x94OCO(cyclohexane), xe2x80x94Oxe2x80x94COCHxe2x95x90CH2, xe2x80x94Oxe2x80x94CO-Phenyl, xe2x80x94O-(2-furoyl), xe2x80x94O-(N-benzo-(2R,3S)-3-phenylisoserine), xe2x80x94O-cinnamoyl, xe2x80x94O-(acetyl-phenyl), xe2x80x94O-(2-thiophenesulfonyl), xe2x80x94Sxe2x80x94(C1-C6 alkyl), xe2x80x94SH, xe2x80x94S-Phenyl, xe2x80x94S-Benzyl, xe2x80x94S-furfuryl, xe2x80x94NH2, xe2x80x94N3, xe2x80x94NHCOCH3, xe2x80x94NHCOCH2Cl, xe2x80x94NHCOCH2CH3, xe2x80x94NHCOCF3, xe2x80x94NHCOCH(CH3)2, xe2x80x94NHCOC(CH3)3, xe2x80x94NHCO(cyclopropane), xe2x80x94NHCO(cyclohexane), xe2x80x94NHCOCHxe2x95x90CH2, xe2x80x94NHCO-Phenyl, xe2x80x94NH(2-furoyl), xe2x80x94NH-(N-benzo-(2R,3S)-3-phenylisoserine), xe2x80x94NH-(cinnamoyl), xe2x80x94NH-(acetyl-phenyl), xe2x80x94NH-(2-thiophenesulfonyl), xe2x80x94F, xe2x80x94Cl, and xe2x80x94CH2CO2H. R4 is a radical selected from the group represented by the formulas: 
However, there is a proviso that if R3 is either methyl or hydrogen and R4 is represented by the following formula: 
then R1 and R2 cannot be simultaneously hydrogen. Preferred epothilone analogs of this aspect of the invention include compounds represented by the following structures: 
Another aspect of the invention is directed to an epothilone analog represented by the following structure: 
In a preferred embodiment, n is one. However, in alternative embodiments n may be as large as five. R1 is a radical selected from the group consisting of hydrogen, tert-butyldimethylsilyl, trimethylsilyl, methyl, acetyl, benzoyl, and tert-butoxycarbonyl. R2 is a radical selected from the group consisting of hydrogen, tert-butyldimethylsilyl, trimethylsilyl, methyl, acetyl, benzoyl, and tert-butoxycarbonyl. R3 is a radical selected from the group consisting of hydrogen, methyl, xe2x80x94CHO, xe2x80x94COOH, xe2x80x94CO2Me, xe2x80x94CO2(tert-butyl), xe2x80x94CO2(iso-propyl), xe2x80x94CO2(phenyl), xe2x80x94CO2(benzyl), xe2x80x94CONH(furfuryl), xe2x80x94CO2(N-benzo-(2R,3S)-3-phenylisoserine), xe2x80x94CONH(methyl)2, xe2x80x94CONH(ethyl)2, xe2x80x94CONH(benzyl), and xe2x80x94CH2R5. R5 is a radical selected from the group consisting of xe2x80x94OH, xe2x80x94O-Trityl, xe2x80x94O-(C1-C6 alkyl), xe2x80x94O-benzyl, xe2x80x94O-allyl, xe2x80x94Oxe2x80x94COCH3, xe2x80x94Oxe2x80x94COCH2Cl, xe2x80x94Oxe2x80x94COCH2CH3, xe2x80x94Oxe2x80x94COCF3, xe2x80x94Oxe2x80x94COCH(CH3)2, xe2x80x94Oxe2x80x94COC (CH3)3, xe2x80x94Oxe2x80x94CO(cyclopropane), xe2x80x94OCO(cyclohexane), xe2x80x94Oxe2x80x94COCHxe2x95x90CH2, xe2x80x94Oxe2x80x94CO-Phenyl, xe2x80x94O-(2-furoyl), xe2x80x94O-(N-benzo-(2R,3S)-3-phenylisoserine), xe2x80x94O-cinnamoyl, xe2x80x94O-(acetyl-phenyl), xe2x80x94O-(2-thiophenesulfonyl), xe2x80x94S-(C1-C6 alkyl), xe2x80x94SH, xe2x80x94S-Phenyl, xe2x80x94S-Benzyl, xe2x80x94S-furfuryl, xe2x80x94NH2, xe2x80x94N3, xe2x80x94NHCOCH3, xe2x80x94NHCOCH2Cl, xe2x80x94NHCOCH2CH3, xe2x80x94NHCOCF3, xe2x80x94NHCOCH(CH3)2, xe2x80x94NHCOC(CH3)3, xe2x80x94NHCO(cyclopropane), xe2x80x94NHCO(cyclohexane), xe2x80x94NHCOCHxe2x95x90CH2, xe2x80x94NHCO-Phenyl, xe2x80x94NH(2-furoyl), xe2x80x94NH-(N-benzo-(2R,3S)-3-phenylisoserine), xe2x80x94NH-(cinnamoyl), xe2x80x94NH-(acetyl-phenyl), xe2x80x94NH-(2-thiophenesulfonyl), xe2x80x94F, xe2x80x94Cl, and xe2x80x94CH2CO2H. R4 is a radical selected from the group represented by the formulas: 
However, there is a proviso that, if R3 is selected from the group consisting of methyl and hydrogen and R4 is represented by the following formula: 
Then R1 and R2 cannot be simultaneously hydrogen. Preferred embodiments of this aspect of the invention include epothilone analogs represented by the following structure: 
Another aspect of the invention is directed to an epothilone analog represented by the following structure: 
In the above structure, R1 is a radical selected from the group consisting of hydrogen, tert-butyldimethylsilyl, trimethylsilyl, methyl, acetyl, benzoyl, and tert-butoxycarbonyl. R2 is a radical selected from the group consisting of hydrogen, tert-butyldimethylsilyl, trimethylsilyl, methyl, acetyl, benzoyl, and tert-butoxycarbonyl. R3 is a radical selected from the group consisting of hydrogen and methyl. R4 is a radical selected from the group represented by the formulas: 
R5 is a radical selected from the group consisting of hydrogen, methylene and methyl. R6 is a radical selected from the group consisting of hydrogen, methylene and methyl. R7 is a radical selected from the group consisting of hydrogen and methyl. However, there are several provisos. If R5 is methylene, then R6 is methylene. If R5 and R6 are methylene, then R5 and R6 are chemically bonded to each other through a single bond xe2x80x9caxe2x80x9d. If R5 and R6 are selected from the group consisting of hydrogen and methyl, then the single bond xe2x80x9caxe2x80x9d is absent. If R3 is selected from the group consisting of methyl and hydrogen and R4 is represented by the formula: 
then R1 and R2 cannot be simultaneously hydrogen.
Another aspect of the invention is directed to an epothilone analog represented by the following structure: 
In this embodiment, R1 is a radical selected from the group consisting of hydrogen, tert-butyldimethylsilyl, trimethylsilyl, methyl, acetyl, benzoyl, and tert-butoxycarbonyl. R2 is a radical selected from the group consisting of hydrogen, tert-butyldimethylsilyl, trimethylsilyl, methyl, acetyl, benzoyl, and tert-butoxycarbonyl. R3 is a radical selected from the group consisting of hydrogen and methyl. R4 is a radical selected from the group represented by the formulas: 
R5 is a radical selected from the group consisting of hydrogen, methylene and methyl. R6 is a radical selected from the group consisting of hydrogen, methylene and methyl. R7 is a radical selected from the group consisting of hydrogen and methyl. However, there are several provisos. If R5 is methylene, then R6 is methylene. If R5 and R6 are methylene, then R5 and R6 are chemically bonded to each other through a single bond xe2x80x9caxe2x80x9d. If R5 and R6 are selected from the group consisting of hydrogen and methyl then the single bond xe2x80x9caxe2x80x9d is absent. If R3 is selected from the group consisting of methyl and hydrogen and R4 is represented by the formula: 
then R1 and R2 cannot be simultaneously hydrogen. Preferred embodiments of this aspect of the invention include compounds represented by the following structures:
Another aspect of the invention is directed to a macrolactonization procedure for synthesizing epothilone and epothilone analogs represented by the following structure: 
wherein R1 may be hydrogen, tert-butyldimethylsilyl, trimethylsilyl, methyl, acetyl, benzoyl, or tert-butoxycarbonyl; wherein R2 may be hydrogen, tert-butyldimethylsilyl, trimethylsilyl, methyl, acetyl, benzoyl, or tert-butoxycarbonyl; wherein R3 may be hydrogen, methyl, xe2x80x94CH2OH, xe2x80x94CH2Cl, or xe2x80x94CH2CO2H; wherein R4 is one of the radicals represented by the following formulas: 
The synthesis may be initiated by condensing a keto acid represented by the following structure: 
with an aldehyde represented by the following structure: 
wherein R5 may be tert-butyldimethylsilyl or trimethylsilyl, for producing a carboxylic acid with a free hydroxyl moiety represented by the following structure: 
The synthesis is then continued by derivatizing the free hydroxyl moiety of the above carboxylic acid with a derivatizing agent represented by the formula R2xe2x80x94X wherein R2xe2x80x94X may be tert-butyldimethylsilyl chloride, tert-butyldimethylsilyl triflate, trimethylsilyl chloride, trimethylsilyl triflate, methyl iodide, methyl sulfate, acetic anhydride, acetic acid, acetyl chloride, benzoic acid, benzoyl chloride, or 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile for producing a derivatized carboxylic acid represented by the following structure: 
The R5 protected hydroxyl moiety of the above derivatized carboxylic acid is then regioselectively deprotected for producing a hydroxy acid with the following structure: 
The above hydroxy acid is then macrolactonized for producing a macrolide with the following structure: 
The synthesis is then completed by epoxidizing the above macrolide for producing the epothilone or epothilone analog.
Further modes of this aspect of the invention are directed to each of the individual steps of the above synthetic macrolactionization procedure and to each of the chemical intermediates employed therein.
Another aspect of the invention is directed to a metathesis approach to synthesizing epothilone and epothilone analogs represented by the following structure: 
wherein R1 may be hydrogen, tert-butyldimethylsilyl, trimethylsilyl, methyl, acetyl, benzoyl, or tert-butoxycarbonyl; wherein R2 may be hydrogen, tert-butyldimethylsilyl, trimethylsilyl, methyl, acetyl, benzoyl, or tert-butoxycarbonyl; wherein R4 is one of the radicals represented by the following formulas: 
The synthetic protocol is initiated by condensing a keto acid represented by the following structure: 
with an aldehyde represented by the following structure: 
wherein R3 may be hydrogen or (CH2)n-(solid phase support), for producing a carboxylic acid with a free hydroxyl moiety represented by the following structure: 
Alternative preferred solid supports include Merrifield resin, PEG-polystyrene, hydroxymethyl polystyrene, formyl polystyrene, aminomethyl polystyrene, or phenolic polystyrene.
The above carboxylic acid is then esterified with a secondary alcohol represented by the following structure: 
for producing an ester with a free hydroxyl moiety represented by the following structure: 
The synthesis is then continued by derivatizing the free hydroxyl moiety of the above ester with a derivatizing agent represented by the formula R2xe2x80x94X wherein R2xe2x80x94X may be tert-butyldimethylsilyl chloride, tert-butyldimethylsilyl triflate, trimethylsilyl chloride, trimethylsilyl triflate, methyl iodide, methyl sulfate, acetic anhydride, acetic acid, acetyl chloride, benzoic acid, benzoyl chloride, or 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile for producing a derivatized ester represented by the following structure: 
The above derivatized ester is then metathesized with an organo-metallic catalyst for producing a macrolide with the following structure: 
Preferred organo-metallic catalyst include bis(tricyclohexylphosphine)benzylidine ruthenium dichloride or 2,6-diisopropylphenylimido neophylidenemolybdenum bis(hexafluoro-t-butoxide).
The above macrolide is then epoxidized for producing the epothilone analog.
Further modes of this aspect of the invention are directed to each of the individual steps of the above synthetic metathesis procedure and to each of the chemical intermediates employed therein.
Another aspect of the invention is directed to a metathesis approach to synthesizing an epothilone analog represented by the following structure: 
wherein R1 may be hydrogen, tert-butyldiphenylsilyl, tert-butyldimethylsilyl, trimethylsilyl, methyl, acetyl, benzoyl, tert-butoxycarbonyl or a radical represented by the following formulas: 
and wherein R2 may be hydrogen, tert-butyldimethylsilyl, trimethylsilyl, methyl, acetyl, benzoyl, or tert-butoxycarbonyl.
The synthesis is initiated by esterifying a keto acid presented by the following structure: 
with an alcohol represented by the following structure: 
for producing an ester represented by the following structure: 
Then, the above ester is condensed with an aldehyde represented by the following structure: 
for producing a bis-terminal olefin with the following structure: 
The synthesis is then continued by metathesizing the above bis-terminal olefin with an organo-metallic catalyst for producing a macrocyclic lactone with a free hydroxyl moiety represented by the following structure: 
Preferred organo-metallic catalysts include bis (tricyclohexylphosphine)benzylidine ruthenium dichloride, or 2,6-diisopropylphenylimido neophylidenemolybdenum bis (hexafluoro-t-butoxide).
The free hydroxyl of the above macrocyclic lactone is then derivatized with a derivatizing agent represented by the formula R2xe2x80x94X wherein R2xe2x80x94X may be hydrogen, tert-butyldimethylsilyl chloride, tert-butyldimethylsilyl triflate, trimethylsilyl chloride, trimethylsilyl triflate, methyl iodide, methyl sulfate, acetic anhydride, acetic acid, acetyl chloride, benzoic acid, benzoyl chloride, or 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile for producing a derivatized macrolide with the following structure: 
The synthesis is then completed by epoxidizing the above derivatized macrolide for producing the epothilone analog.
Further modes of this aspect of the invention are directed to each of the individual steps of the above synthetic metathesis procedure and to each of the chemical intermediates employed therein.
Another aspect of the invention is directed to a method employing a metathesis approach for synthesizing an epothilone analog represented by the following structure: 
wherein R1 may be hydrogen, tert-butyldimethylsilyl, trimethylsilyl, methyl, acetyl, benzoyl, or tert-butoxycarbonyl; wherein R2 is one of the radicals represented by the following structures: 
The synthesis is initiated by condensing a keto acid represented by the following structure: 
with an aldehyde represented by the following structure: 
for producing a carboxylic acid with a free hydroxyl moiety represented by the following structure: 
The free hydroxyl moiety of the above carboxylic acid is then derivatized with a derivatizing agent represented by the formula R1xe2x80x94X wherein R1xe2x80x94X may be tert-butyldimethylsilyl chloride, tert-butyldimethylsilyl triflate, trimethylsilyl chloride, trimethylsilyl triflate, methyl iodide, methyl sulfate, acetic anhydride, acetic acid, acetyl chloride, benzoic acid, benzoyl chloride, or 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile for producing a derivatized carboxylic acid represented by the following structure: 
The synthesis is then continued by esterifying the derivatized carboxylic acid of said Step B with an alcohol represented by the following structure: 
for producing a bis-terminal olefin with the following structure: 
The above bis-terminal olefin is then metathesized with an organo-metallic catalyst for producing a macrocyclic lactone with the following structure: 
Preferred organo-metallic catalysts include bis(tricyclohexylphosphine)benzylidine ruthenium dichloride, or 2,6-diisopropylphenylimido neophylidenemolybdenum bis(hexafluoro-t-butoxide).
The synthesis is then completed by epoxidizing the above macrocyclic lactone for producing the epothilone analog.
Further modes of this aspect of the invention are directed to each of the individual steps of the above synthetic metathesis procedure and to each of the chemical intermediates employed therein.
Another aspect of the invention is directed to a method employing a macrolatonization approach for synthesizing an epothilone analog represented by the following structure: 
wherein R1 may be hydrogen, tert-butyldimethylsilyl, trimethylsilyl, methyl, acetyl, benzoyl, or tert-butoxycarbonyl; wherein R2 may be hydrogen, tert-butyldimethylsilyl, trimethylsilyl, methyl, acetyl, benzoyl, or tert-butoxycarbonyl; wherein R3 may be hydrogen, methyl, xe2x80x94CH2OH, xe2x80x94CH2Cl, or xe2x80x94CH2CO2H; wherein R4 is one of the radicals represented by the following formulas: 
The synthesis is initiated by condensing a keto acid represented by the following structure: 
wherein R6 may be tert-butyldimethylsilyl, trimethylsilyl, tert-butyldiphenylsilyl, methyl, hydrogen, triethylsilyl, or benzyl; with an aldehyde represented by the following structure: 
wherein R5 may be tert-butyldimethylsilyl or trimethylsilyl, for producing a xcex2-hydroxy ketone with a free hydroxyl moiety and a R6 protected hydroxyl moiety represented by the following structure: 
The free hydroxyl moiety of the above xcex2-hydroxy ketone is then derivatized with a derivatizing agent represented by the formula R2xe2x80x94X wherein R2xe2x80x94X may be tert-butyldimethylsilyl chloride, tert-butyldimethylsilyl triflate, trimethylsilyl chloride, trimethylsilyl triflate, methyl iodide, methyl sulfate, acetic anhydride, acetic acid, acetyl chloride, benzoic acid, benzoyl chloride, or 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile for producing a derivatized xcex2-hydroxy ketone represented by the following structure: 
The R6 protected hydroxyl moiety of the above derivatized xcex2-hydroxy ketone is then regioselectively deprotected for producing a terminal alcohol with the following structure: 
The above terminal alcohol is then oxidized for producing a derivatized carboxylic acid with a R5 protected hydroxyl moiety with the following structure: 
The synthesis is then continued by regioselectively deprotecting the R5 protected hydroxyl moiety of the derivatized carboxylic acid of-said step D for producing a hydroxy acid with the following structure: 
The above hydroxy acid is then macrolactonized for producing a macrolide with the following structure: 
The synthesis is then completed by epoxidizing the above macrolide for producing the epothilone analog.
Further modes for this aspect of the invention are directed to each of the individual steps of the above synthetic macrolactonization procedure and to each of the chemical intermediates employed therein.
Another aspect of the invention is directed to a process for synthesizing an epothilone analog having an epoxide and an aromatic substituent. In the first step of this process, a first epothilone intermediate and an aromatic stannane are coupled by means of a Stille coupling reaction to produce a second epothilone intermediate. The first epothilone intermediate has a vinyl iodide moiety to which the aromatic stannane is coupled for producing the second epothilone intermediate. Preferred embodiments of the first epothilone intermediate are represented by the following structure: 
In the above structure, R2 is a radical selected from hydrogen, tert-butyldimethylsilyl, trimethylsilyl, methyl, acetyl, benzoyl, or tert-butoxycarbonyl. R3 is a radical selected from hydrogen, tert-butyldimethylsilyl, trimethylsilyl, methyl, acetyl, benzoyl, or tert-butoxycarbonyl. In a preferred embodiment, the aromatic stannane is a compound represented by one of the following structures: 
The second epothilone intermediate has the aromatic substituent and a cis olefin. In a preferred embodiment, the second epothilone intermediate is represented by the following structure: 
R1 is one of the radicals represented by the following formulas: 
In the second step of this process, the cis olefin of the second epothilone intermediate is epoxidized to produce the epothilone analog. In a preferred embodiment, the epothilone analog is represented by the following structure: 
In a preferred mode of the above process for synthesizing an epothilone analog, there are several additional steps that are performed prior to the Stille coupling step. The first of the additional steps involves the condensation of a keto acid represented by the following structure: 
with an aldehyde represented by the following structure: 
wherein R4 may be hydrogen or (CH2)n-(solid phase support) for producing a carboxylic acid represented by the following structure: 
Then, the above carboxylic acid is esterified with a secondary alcohol represented by the following structure: 
for producing an ester with a free hydroxyl moiety represented by the following structure: 
Then, there is an optional step. The free hydroxyl moiety of the above ester may be derivatized with a derivatizing agent. Preferred derivatizing agents include tert-butyldimethylsilyl chloride, tert-butyldimethylsilyl triflate, trimethylsilyl chloride, trimethylsilyl triflate, methyl iodide, methyl sulfate, acetic anhydride, acetic acid, acetyl chloride, benzoic acid, benzoyl chloride, or 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile for producing an optionally derivatized ester represented by the following structure: 
Finally, the above optionally derivatized ester is metathesized with an organo-metallic catalyst for producing the above indicated first epothilone analog.
Another aspect of the invention is directed to the use of each of the above metathesis approaches for synthesizing libraries of epothilone analogs. In this mode, a combinatorial approach is employed for synthesizing libraries of epothilone analogs having various combinations of the preferred R groups.